CN1017151B - Processes for preparing naphthothiazepine derivative - Google Patents

Abstract

A novel naphthpthiazepine derivative of the formula wherein R<1> is a lower alkoxy group, R<2> is hydrogen atom or a lower alkanoyl group, and R<3> and R<4> are the same or different and hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable acid addition salt thereof, are disclosed. Said derivative (I) and a salt thereof are useful as hypotensive agents and/or coronary or cerebral vasodilators.

Description

（naphthothiazepine）衍生物及其制备方法。更进一步讲，它涉及一种结构式为：The present invention relates to a novel naphthothiazapine

(naphthothiazepine) derivatives and methods for their preparation. Furthermore, it involves a structure of the formula:

衍生物或其一种药物学上可接受的酸加成盐，其中R¹为一种低级烷氧基基团，R²为氢原子或一种低级链烷酰（alka-noyl）基团，且R³和R⁴为相同的或不同的，并为氢原子或一种低级烷基基团。naphthothiazepines

derivative or a pharmaceutically acceptable acid addition salt thereof, wherein R ¹ is a lower alkoxy group, R ² is a hydrogen atom or a lower alkanoyl (alka-noyl) group, And R ³ and R ⁴ are the same or different, and are a hydrogen atom or a lower alkyl group.

衍生物如（±）-顺式-2-（4-甲氧基苯基）-3-乙酰氧基-5-〔2-（二甲基氨基）乙基〕-2，3-二氢-萘并〔1，2-b〕-1，5-硫杂氮杂

-4（5H）-酮显示降血压效应，且作为钙通道阻滞剂（calcium channel blockers）是有用的。U.S. Patent 4,652,561 discloses naphthiazapine

Derivatives such as (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro- Naphtho[1,2-b]-1,5-thiazapine

-4(5H)-ketones show hypotensive effects and are useful as calcium channel blockers.

衍生物（Ⅰ）和其一种盐显示较强的降血压效应和血管舒张效应，且在各种血管疾病的治疗和预防方面更有用。Compared with said known compounds, the novel naphthothiaazepines of the present invention

The derivative (I) and a salt thereof exhibit a strong hypotensive effect and a vasodilatory effect, and are more useful in the treatment and prevention of various vascular diseases.

Examples of the compound (I) of the present invention include those compounds wherein R ¹ is an alkoxy group of 1 to 6 carbon atoms, R ² is a hydrogen atom or an alkanoyl group of 2 to 6 carbon atoms group, and ^R3 and ^R4 are a hydrogen atom or an alkyl group of 1 to 6 carbon atoms. Among them, preferred examples include those compounds of formula (I), wherein R ¹ is an alkoxy group of 1 to 4 carbon atoms, R ² is a hydrogen atom or a chain of 2 to 4 carbon atoms An alkanoyl group, R ³ is an alkyl group of 1 to 4 carbon atoms, and R ⁴ is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms.

According to the present invention, compound (I) can be represented by a structural formula:

(II)

A compound or a salt thereof, wherein ^R1 and ^R2 are as defined above, and a structural formula is:

A compound or a salt thereof, wherein R ³ and R ⁴ are as defined above, and X ¹ is prepared by condensation of a halogen atom.

The compound (I) of the present invention, wherein R ² is a lower alkanoyl group can also be represented by a structural formula:

（Ⅰ-A）

(Ⅰ-A)

A compound or a salt thereof, wherein R ¹ , R ³ and R ⁴ are as defined above, and a structural formula is:

or a reactive derivative thereof, wherein R ^2' is prepared by condensation of a lower alkyl group.

On the other hand, the compound (I) of the present invention, wherein R ³ is a lower alkyl group, and R ⁴ is a hydrogen atom, can be obtained by a structural formula:

（Ⅰ-B）

(Ⅰ-B)

A compound or a salt thereof, wherein R ^3' and R ^4' are both a lower alkyl group, and R ¹ and R ² are as defined above, reacted with a reactive derivative of haloformic acid, and then Prepared by treating the product with water, a lower alkanol or a mixture thereof or with zinc in a lower alkanoic acid.

If necessary, the starting compound (II) can be used in the above reaction in the form of an alkali metal salt (for example, sodium salt or potassium salt), and, if necessary, the starting compound (III) and compound (I-A) and (I-B) may be present as an acid addition salt such as an inorganic acid addition salt (for example, hydrochloride or hydrobromide) or an organic acid addition salt (for example, maleate, fumarate or mesylate) for the above reaction.

The condensation of compound (II) or a salt thereof with compound (III) or a salt thereof can be carried out in a suitable solvent in the presence or absence of a basic reagent. When the compound (II) is used in free form, said condensation is preferably carried out in the presence of a basic reagent. Examples of suitable alkaline reagents include an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate) and an alkali metal hydrogenation substances (for example, sodium hydride), etc. It is preferred to carry out the condensation at 20 to 100°C, especially 25 to 70°C.

The condensation of compound (I-A) or a salt thereof with compound (IV) can be carried out in a condensing agent in the presence of a suitable solvent. Examples of suitable condensing agents include dicyclohexylcarbo(3)diimide, N,N-diisopropylcarbo(3)diimide, and N,N'-di-p-tolylcarbodiimide, etc. . It is preferred to carry out the reaction at 0 to 30°C.

On the other hand, the condensation of the compound (I-A) with the reactive derivative of the compound (IV) can be carried out in a suitable solvent in the presence or absence of an acidic acceptor. Examples of suitable reactive derivatives include the corresponding acid halides (e.g. chlorides, bromides) anhydrides, mixed anhydrides (e.g. ethoxycarbonyl esters, isopropoxycarbonyl esters, isobutoxycarbonyl esters) and active esters (e.g. p-nitrophenyl ester 2,4,5-trichlorophenyl ester 2,4,6-trichlorophenyl ester, N-hydroxysuccinimide ester, 1-benzotriazole ester) wait. Examples of suitable acid acceptors include pyridine, triethylamine, an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydroxide, and the like. It is preferred to carry out the reaction at a temperature of 0 to 100°C.

The reaction of compound (I-B) with a reactive derivative of haloformic acid can be carried out in a suitable solvent in the presence or absence of a base. Examples of reactive derivatives of the haloformic acid include the corresponding acid halides (e.g., carbon difluoride, carbon dichloride, carbon dibromide, and carbon diiodide), and haloformic acid mono-, bis- Or trihalo-lower alkyl esters (for example, trichloromethyl chloroformate, α-chloroethyl chloroformate, β,β,β-trichloroethyl chloroformate). Examples of a base include triethylamine, pyridine, -picoline, 2,6-lutidine, tetramethylurea, hexamethylphosphoric triamide, quinoline and the like. It is preferably carried out at 0°C to 140°C.

Compound (I), wherein ^R3 is a lower alkyl group, and ^R4 is a hydrogen atom, can be obtained by treating with water, a lower alkanol (for example, methanol) or a mixture thereof product obtained. It is preferably carried out at 20 to 120°C.

When α-chloroethyl chloroformate or β,β,β-trichloroethyl chloroformate is used as haloalkyl ester of haloformic acid, compound (I), wherein ^R3 is a Lower alkyl groups with ^R4 being a hydrogen atom can also be obtained by treating the product thus obtained with zinc (for example, zinc powder) in a lower alkanoic acid such as acetic acid.

Examples of suitable solvents preferably used in the above reaction are benzene, dioxane, methylene chloride, chloroform, acetone, acetonitrile, ethyl acetate, dimethylformamide and the like.

骨架的2-和3-号位上的二个不对称碳原子，可以以四种旋光异构体〔即，（+）-顺式，（-）顺式，（+）-反式和（-）反式异构体〕的形式存在。然而，由于所有的上述反应是在无外消旋作用下进行的，本发明的化合物（Ⅰ），以一种光学活化的形式，可通过用化合物（Ⅱ）的一种光学异构体作为起始化合物而容易地获得。The compound (I) of the present invention, due to the naphthothiazapine

The two asymmetric carbon atoms on the 2- and 3-positions of the skeleton can be in four optical isomers [ie, (+)-cis, (-) cis, (+)-trans and ( -) exists in the form of trans isomer]. However, since all the above-mentioned reactions are carried out without racemization, the compound (I) of the present invention, in an optically active form, can be obtained by using an optical isomer of the compound (II) as a starting compounds are readily available.

The thus obtained compound (I) of the present invention can be used in pharmaceutical applications in the free form or in the form of a pharmaceutically acceptable acid addition salt thereof. Examples of salts of compound (I) include inorganic acid addition salts such as hydroxide, hydrobromide, hydroiodide, perchlorate, sulfate or phosphate, and organic acid addition salts and oxalate, horse tonate, fumarate, tartrate, mesylate or succinate. These salts can be easily obtained, for example, by treating the compound (I) with an acid in a conventional manner.

Because of the effective hypotensive effect, and cerebral vasodilation effect and coronary vasodilation effect, the compound (I) of the present invention and a pharmaceutically acceptable acid addition salt are used for the treatment and prevention of hypotension, brain diseases such as Cerebral vasospasm, cerebral ischemia and cerebral infarction, and heart disorders such as angina and myocardial infarction (formation).

Furthermore, although known vasodilators such as Verapamil are known to delay atrioventricular conduction time by inhibiting atrioventricular conduction, and sometimes induce arrhythmia due to this conduction disturbance, the compound (I) of the present invention and one of its Salts are characterized in that they have fewer adverse side effects such as less inhibition of atrioventricular conduction or less reduction in heart rate.

Furthermore, the compound of the present invention and a salt thereof have a potent inhibitory effect on platelet aggregation and are very useful for the treatment of cerebral diseases such as cerebral vasospasm, cerebral ischemia and cerebral infarction.

The compound (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof can be used in the form of a pharmaceutical preparation containing a compound suitable for oral or parenteral administration. pharmaceutical excipients. Examples of suitable excipients include starch, lactose, glucose, potassium phosphate, corn starch, acacia, stearic acid and other customary pharmaceutical excipients. The pharmaceutical preparations can be administered in solid dosage forms such as tablets, pills, capsules and suppositories, etc., or in liquid dosage forms such as solutions, suspensions and emulsions. Further, when administered parenterally, the pharmaceutical preparations can be administered in the form of injections.

The daily dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may vary depending on the route of administration, the age, body weight or condition of the patient and the severity of the disease to be treated. However, in general, a preferred daily dose of compound (I) or a salt thereof is usually in the range of 0.05 to 10 mg/kg, especially about 0.5 to 10 mg/kg in the case of oral administration, or In the case of enteral administration (eg, intravenous injection) 0.05 to 2 mg/kg.

Concomitantly, the starting compound (II) of the present invention can, for example, be obtained by 2-aminonaphthalene-2-thiol (thiol) and a structural formula:

Glycidyl esters, wherein R is an ester residue, and ^R is prepared by condensation as defined above.

Experiment 1

hypotensive activity

(method)

A test compound dissolved or suspended in water was administered orally at a dose of 30 mg/kg to overnight fasted spontaneously hypotensive rats (SHR) and tail plethysmography (scanning) technique (Laboratory and Clinical Medicine Journal, Vol. 78 (1971), p. 957) The systolic blood pressure of the rat was measured at regular intervals. The hypotensive activity of the test compound was estimated in terms of "lowering blood pressure (ΔmmHg)", which was calculated by the following formula.

Reduction in blood pressure (△ mmHg) =

(result)

The results are shown in Table 1 below.

Table 1

Decrease in blood pressure (△ mm Hg)

time after medication

1 hour 2 hours 5 hours

1. Test compound ^* 58.3±8.8 51.3±7.7 34.0±6.2

*): Chemical name of the test compound:

-4（5H）-酮延胡索酸盐。(±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-naphtho[ 2,1-b]-1,5-thiazapine

-4(5H)-keto fumarate.

Example 1

(1) A 7.86 g 1-aminonaphthalene-2-thiol, 12.16 g 3-(4-methoxyphenyl) glycidic acid methyl (base) ester (methyl 3-(4- methoxyphenyl) glycidate) and 80 ml of toluene. After the reaction was complete, the reaction mixture was concentrated. Diisopropyl ether was added to the oily residue. The precipitated crystals were collected by filtration and recrystallized from methanol to give 6.49 g (38%) of (±)-threo-3-(1-amino-2-naphthyl)thio-3-(4-methoxy phenyl)-2-hydroxypropanoic acid methyl (yl) ester.

Melting point: 131.5-135°C

Mass Spectrum (Mass) (m/e): 383 (M ⁺ )

IR (medical lubricant (Nujol, cm ^-1 ): 3500, 3420, 3120, 1730

-4（5H）-酮。(2) At room temperature, a solution of 4.0 g of the product obtained above in 2.60 g of a 5% aqueous sodium hydroxide solution, 10 ml of ethanol and 2 ml of tetrahydrofuran was stirred for 2 hours and washed with 10% hydrochloric acid Acidify (pH 2-3), and extract with chloroform. The extracts were combined, washed with water, dried and concentrated. The residue was recrystallized from ethanol to give 3.08 (±)-threo-3-(1-amino-2-naphthyl)thio-3-(4-methoxyphenyl)-2-hydroxypropanoic acid) Melting point: 164-165°C (decomposition). A suspension of 2.8 g of the product obtained above in 140 ml of xylene was refluxed for 7 hours. After cooling, the precipitated crystals were recrystallized from a mixture of chloroform and ethanol to give 1.0 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-di Hydrogen-naphtho[2,1-b]-1,5-thiazapine

-4(5H)-one.

Melting point: 263-267°C

Mass (m/e): 351 (M ⁺ )

IR (Nujol, cm ^-1 : 3520, 3200, 3100, 3080, 3060, 1660

-4（5H）-酮。(3) A mixture of 3.52 g of the product obtained above, 1.17 g of 2-(dimethylamino)ethyl chloride hydrochloride and 3.24 g of potassium carbonate was refluxed in 135 ml of acetone. After the reaction was complete, inorganic materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water, dried, and concentrated to dryness. The residue thus obtained was purified by silica gel column chromatography [solvent: a mixture of chloroform and methanol (30:1)] to give 2.01 g of (±)-cis-2-(4-methoxyphenyl )-3-Hydroxy-5-[2-(dimethoxy)ethyl]2,3-dihydro-naphtho[2,1-b]-1,5-thiazapine

-4(5H)-one.

The product is treated with fumaric acid and recrystallized from ethanol to give the corresponding fumarate salt.

Melting point: 216-218°C (decomposition)

Mass (m/e): 422 (M ⁺ )

IR (Nujol, cm ^-1 ): 3460, 3050, 1730, 1660

Example 2

-4（5H）-酮延胡索酸盐。2.32 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-naphtho [2,1-b]-1,5-thiazapine -4(5H)-Kone was added to 70 ml of acetic acid-acetic anhydride (1:1), and the mixture was refluxed. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was dissolved in a small amount of ethanol, and 1.1 equivalents of fumaric acid was added to the solution. The precipitated crystals were recrystallized from ethanol to give 2.0 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethane Base]-2,3-dihydro-naphtho[2,1-b]-1,5-thiazapine

-4(5H)-keto fumarate.

Melting point: 216-218°C

Mass (m/e): 464 (M ⁺ )

IR (Nujol, cm ^-1 ): 3060, 3040, 2600-2300, 1740, 1690

Example 3

-4（5H）-酮延胡索酸盐中，并用氯仿萃取该溶液。该萃取液用水洗涤，干燥并浓缩。将残余的含油产物溶于10毫升甲苯中，并向其中加入192毫克三乙胺。然后，在冰冷却下，将403毫克氯代甲酸三氯代甲基酯加至该混合物中，并在室温下通宵搅拌该混合物。浓缩该反应混合物，并将残余含油产物溶于一种醚和氯仿（1∶1）的混合物中。该溶液依次用10%的盐酸和水洗涤。有机层干燥并浓缩。将残余的含油产物溶于10毫升乙腈中，并向其中加入10毫升水。回流此混合物40分钟。反应之后，蒸发该混合物以除以乙腈。该残余的水溶液用碳酸氢钠制成碱性，并用氯仿萃取。该萃取液用水洗涤，干燥并浓缩。将该残余的产物转化为延胡索酸盐，并从乙醇中重结晶而给出632毫克（±）-顺式-2-（4-甲氧基苯基）-3-乙酰氧基-5-〔2-（甲基氨基）乙基〕-2，3-二氢-萘并〔2，1-b〕-1，5-硫杂氮杂 -4（5H）-酮延胡索酸盐。An aqueous solution of potassium carbonate was added to 788 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl] -2,3-Dihydro-naphtho[2,1-b]-1,5-thiazapine

-4(5H)-keto fumarate, and the solution was extracted with chloroform. The extract was washed with water, dried and concentrated. The residual oily product was dissolved in 10 ml of toluene, and 192 mg of triethylamine was added thereto. Then, 403 mg of trichloromethyl chloroformate was added to the mixture under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residual oily product was dissolved in a mixture of ether and chloroform (1:1). The solution was washed successively with 10% hydrochloric acid and water. The organic layer was dried and concentrated. The residual oily product was dissolved in 10 ml of acetonitrile, and 10 ml of water was added thereto. The mixture was refluxed for 40 minutes. After reaction, the mixture was evaporated to divide by acetonitrile. The residual aqueous solution was made basic with sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried and concentrated. The residual product was converted into fumarate and recrystallized from ethanol to give 632 mg of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2 -(Methylamino)ethyl]-2,3-dihydro-naphtho[2,1-b]-1,5-thiazapine -4(5H)-keto fumarate.

Yield: 82%

Melting point: 199-202°C (decomposition)

IR (Nujol, cm ^-1 ): 3060, 3040, 1740, 1680, 1660

Claims (5)

1, a kind of preparation a kind of structural formula is:

(I) naphthothiazepines

derivative or a pharmaceutically acceptable acid addition salt thereof, wherein R ¹ is a lower alkoxy group, R ² is a hydrogen atom or a lower alkanoyl group, and R ³ and ^R4 are the same or different, and are a hydrogen atom or a lower alkyl group, which includes [I] Make a structural formula as:

A compound or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are as defined above, and a structural formula:

A compound or a salt thereof (wherein R ³ and R ⁴ are as defined above, and X ¹ is a halogen atom) condensation, [Ⅱ]-[A] When the product obtained is the structural formula: or a salt thereof, (where ^R3 and ^R4 are as defined above), it may optionally be combined with a structural formula: Condensation of a compound or a reactive derivative thereof (wherein R ^2' is a lower alkanoyl group) to obtain a compound of formula (I) in which ^R is a lower alkanoyl group, [Ⅱ]-[B], when the product obtained is the structural formula:

or a salt thereof, wherein R ^3' and R ^4' are both a lower alkyl group, and R ¹ and R ² are as defined above, making it optionally reactive with a haloformic acid Derivatives are further reacted by treating the product with water, a lower alkanol or mixtures thereof, or with zinc in a lower alkanoic acid to give ^R3 as lower alkyl and ^R4 as hydrogen A compound of formula (I), [III] If necessary, further converting the product into a pharmaceutically acceptable acid addition salt thereof. 2. The preparation method according to claim 1, characterized in that R in it or a pharmaceutically acceptable acid addition salt thereof is an alkoxy group with ¹ to 4 carbon atoms, R ² is a hydrogen atom or an alkanoyl group of 2 to 4 carbon atoms, and R ³ and R ⁴ are the same or different, and are a hydrogen atom or an alkyl group of 1 to 4 carbon atoms. 3. The preparation method according to claim 1, characterized in that in it or one of its pharmaceutically acceptable acid addition salts, ^R1 is a methoxy group, and ^R2 is a hydrogen atom or an acetyl group , R ³ is a methyl group, and R ⁴ is a hydrogen atom or a methyl group. 4. The preparation method according to claim 1, characterized in that (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(di Methylamino)ethyl]-2,3-dihydro-naphtho[2,1-b]-1,5-thiazapine -4(5H)-ketone, or a pharmaceutically acceptable acid addition salt thereof. 5. The preparation method according to claim 1, characterized in that (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[(2-methyl Amino)ethyl-2,3-dihydro-naphtho[2,1-b]-1,5-thiazepine

-4(5H)-ketone, or a pharmaceutically acceptable acid addition salt thereof.